Abstract Biomedical images are typically obtained utilizing optical light or X-rays. Optical light is suitable for thin tissue slices, but not suitable for obtaining quality 3D images of thick tissue. Tissue specimens up to millimeter in thickness provide information about structure, different cell types and their relationships. One of the problems with optical imaging in thick tissue is the scattering of the optical light. X-rays can penetrate thick tissue, but the currently commercially available X-ray microscope imaging systems, such as the XRadia and Rigaku systems, are not optimal for soft tissue imaging. For the Xradia Versa, the lowest energy X-ray spectrum is 30 kVp, which is too high for soft tissue, while in the Xradia Ultra the field of view is only ~60 m, and 3D imaging requires several hours. In the case of the Rigaku system, absorption contrast is too low even at low energies. We propose to deliver an intensity-modulation phase-based soft X-ray microscope for non-destructive synchrotron-quality imaging of intact biological samples with the following features: ? 3D, quantitative and multimodal (phase, attenuation, scatter) images ? Acquisition times more than 10 times shorter than in XRadia systems ? Resolution of hundreds of nm, same as visible light microscopes ? Field of view from 5 mm x 5 mm to 1 mm x 1 mm, resolution from 2 m to less than 0.5 m ? High-contrast images of cell composition ? Imaging tissue/cells in their native hydrated state, with no staining and other disrupting preparation procedures ? Implementing two low energy X-ray sources: 5.4 keV and 8 keV. The user can switch back and forth between the two options, as well as adjust the resolution dynamically This will be realized by combining intensity-modulation X-ray phase-based imaging (IM XPBI) method with two innovations such as cycloidal CT acquisition and lab-based ptychography. The microscope will be installed at Memorial Sloan Kettering Cancer Center and validated with a database of existing tissue samples. The 3D histology results from the proposed microscope will be compared to histology results from conventional imaging modalities to determine efficacy. Tests will also be carried out to study cancer- associated cells in blood, such as circulating tumor cells and giant cancer-associated macrophage-like cells discovered by Creatv MicroTech. Possibility to obtain high- resolution high-contrast 3D images of cells in their native state will enhance our biomedical research and clinical utility to cancer. This novel technology will be helpful for basic, pre-clinical and clinical studies related to many health conditions, such as cancer, osteoporosis, arthritis, cardiovascular disease and will assist with understanding of how these diseases progress and how they can be treated.